Submissions for variant NM_000180.4(GUCY2D):c.2303G>A (p.Arg768Gln)

gnomAD frequency: 0.00001  dbSNP: rs750889782

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Revvity Omics, Revvity	RCV001784301	SCV002018536	likely pathogenic	not provided	2021-10-25	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000678575	SCV003921082	likely pathogenic	Leber congenital amaurosis 1	2023-03-02	criteria provided, single submitter	clinical testing	This variant was identified as compound heterozygous with NM_000180.4:c.2302C>T._x000D_ Criteria applied: PM3_STR, PM5, PM2_SUP, PP3
Labcorp Genetics (formerly Invitae), Labcorp	RCV003768027	SCV004571053	pathogenic	Cone-rod dystrophy 6; Leber congenital amaurosis 1	2023-09-27	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 768 of the GUCY2D protein (p.Arg768Gln). This variant is present in population databases (rs750889782, gnomAD 0.002%). This missense change has been observed in individual(s) with Leber congenital amaurosis (PMID: 21153841, 26047050). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 560463). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GUCY2D protein function. This variant disrupts the p.Arg768 amino acid residue in GUCY2D. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16505055, 17724218, 23035049, 26253563, 26626312). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001003041	SCV005039225	pathogenic	Leber congenital amaurosis	2024-03-22	criteria provided, single submitter	clinical testing	Variant summary: GUCY2D c.2303G>A (p.Arg768Gln) results in a conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251314 control chromosomes. c.2303G>A has been reported in the literature in individuals affected with Leber Congenital Amaurosis (Wang_2015, Haer-Wigman, Wiszniewski_2011). In addition, another missense variatn in the same residue (p.Arg768Trp) has been classified as pathogenic in ClinVar by various submitters. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28224992, 26047050, 21153841). ClinVar contains an entry for this variant (Variation ID: 560463). Based on the evidence outlined above, the variant was classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004760694	SCV005040829	pathogenic	POLR3-related leukodystrophy	2024-03-22	criteria provided, single submitter	clinical testing	Variant summary: POLR3B c.2303G>A (p.Arg768His) results in a non-conservative amino acid change located in the DNA-directed RNA polymerase, subunit 2, hybrid-binding domain (IPR007120) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.4e-05 in 251166 control chromosomes, predominantly at a frequency of 0.00059 within the South Asian subpopulation in the gnomAD database. c.2303G>A has been reported in the literature in the homozygous and compound heterozygous state in individuals affected with POLR3-Related Leukodystrophy (e.g. Saitsu_2011, Parayil Sankaran_2020). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. One laboratory classified the variant as pathogenic, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000678575	SCV000804655	pathogenic	Leber congenital amaurosis 1	2016-09-01	no assertion criteria provided	clinical testing
Sharon lab, Hadassah-Hebrew University Medical Center	RCV001003041	SCV001161098	pathogenic	Leber congenital amaurosis	2019-06-23	no assertion criteria provided	research